Design and docking of novel series of hybrid xanthones as anti-cancer agent to target human DNA topoisomerase 2-alpha
Topoisomerase (topo) IIα is a homodimeric protein catalyzes topological vicissitudes by adding or by soothing super coiling transpiration, occurs in human DNA during DNA replication as an outcome chromosome segregation and condensation occurs during meiosis I and recombination. To prevent the cleavage and religation activity we administered novel hybrid substituted Xanthone series of drugs. The toxicity prediction showed outstanding results which impetus to study its anticancer activities by targeting topoisomerase (topo) IIα. We developed the homology model of the topoisomerase (topo) IIα due to the unavailability of 3D structure in the Protein Data Bank. Structural assessment of the modeled protein and confirmed the quality of the model. The ligands were docked using Autodock4.2 software and binding energy was reported. The compound XM9, XN2, XM7, XLNU and XNS scored lowest binding energy and highest binding affinity. The interaction sites and the hydrogen bond were observed.
Bailly C. Contemporary challenges in the design of Topoisomerase II inhibitors for cancer chemotherapy. Chem Rev. 2012; 112: 3611-40.
Binaschi M, Bigioni M, Cipollone A, Rossi C, Goso C, Maggi CA, Capranico G, Animati F. Anthracyclines: Selected new developments. Curr Med Chem Anti-cancer Agents. 2001; 1: 113-30.
Boehm HJ, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W, Kostrewa D, Kuehne H, Luebbers T, Meunier-Keller N, Mueller F. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J Med Chem. 2000; 43: 2664-74.
Champoux JJ. DNA topoisomerases: Structure, function, and mechanism. Annu Rev Biochem. 2001; 70: 369-413.
Dong KC, Berger JM. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature 2007; 450: 1201-05.
Fortune JM, Prog ON. Topoisomerase II as a target for anti-cancer drugs: When enzymes stop being nice. Prog Nucleic Acid Res Mol Biol. 2000; 64: 221-53.
Heck MM, Earnshaw WC. Topoisomerase II: A specific marker for cell proliferation. J Cell Biol. 1986; 103: 2569-81.
Hu CX, Zuo ZL, Xiong B, Ma JG, Geng MY, Lin LP, Jiang HL, Ding J. Salvicine functions as novel topoisomerase II poison by binding to ATP pocket. Mol Pharmacol. 2006; 70: 1593-601.
Jun KY, Lee EY, Jung MJ, Lee OH, Lee ES, Park Choo HY, Na Y, Kwon Y. Synthesis, biological evaluation, and molecular docking study of 3-(30-heteroatom substituted-20-hydroxy-10-propyloxy) xanthone analogues as novel Topoisomerase IIa catalytic inhibitor. Eur J Med Chem. 2011; 46: 1964-71.
Larsen AK, Escargueil AE, Skladanowski A. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol Ther. 2003; 99: 167-81.
Liu LF. DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem. 1989; 58: 351-75.
Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009; 9: 338-50.
Patil TD, Thakare SV. In silico evaluation of selected triterpene glycosides as a human DNA topoisomerase II alpha (α) inhibitor. Int J Pharm Pharm Sci. 2012; 4: 201-04.
Robinson MJ, Osheroff N. Effects of antineoplastic drugs on the poststrand-passage DNA cleavage/religation equilibrium of topoisomerase II. Biochemistry 1991; 30: 1807-13.
Shen R, Wang P, Tang N. Cytotoxic Activity and DNA-binding Properties of Xanthone Derivatives. J Fluoresc. 2010; 20: 1287-97.
Su QG, Liu Y, Cai YC, Sun YL, Wang B, Xian LJ. Anti-tumour effects of xanthone derivatives and the possible mechanisms of action. Invest New Drugs. 2011; 29: 1230-40.
Vilain N, Tsai-Pflugfelder M, Benoit A, Gasser SM, Leroy D. Modulation of drug sensitivity in yeast cells by the TP-binding domain of human DNA topoisomerase IIa. Nucleic Acids Res. 2003; 31: 5714-22.
Watt PM, Hickson ID. Structure and function of type II DNA topoisomerases. Biochem J. 1994; 303: 681-95.
Wilstermann AM, Osheroff N. Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem. 2003; 3: 321-38.
Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH. Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ. 1991; 2: 209-14.
Copyright (c) 2014 Lalit Mohan Nainwal, Pratap Parida, Aparoop Das, Parth Sarathi Bairy
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).